Furane amino keto compounds



Patented Apr. 3,

UNITED STATES PATENT OFFICE FURANE AMINO KE'EO COMPOUNDS Loren MrLong, Grosse Pointe Woods, and Nickolas D. J enesel, Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Mich, a cor;-

poration of Michigan No Drawing. Application Mamba 19.50,,

- Serial No. 148,755

tion relates to amino ketones of the furane series having the formula,

where R is hydrogen, nitro, halogen or a lower alkyl radical and R is hydrogen, HHY, or an acyl radical. HY being one equivalent of a strong mineral acid such as hydrochloric, hydrobromic,

hydriodic, sulfuric, phosphoric and the like. The

term acyl as used herein includessaturated and unsaturated lower aliphatic acyl, halogen-sub stituted lower aliphatic acyl, carboxy-subs'tituted lower" aliphatic acyl, cyano-substituted lower alia phatic acyl, ether-substituted lower aliphatic acyl, ester-substituted lower aliphatic acyl, benzoyl, substituted benzoyl, araliphatic acyl, furoyl, pyridinoyl and the like radicals.

Our process for obtaining the compounds of the invention may :be diagrammatically illus- I ated a w where X is a halogen atom and R and HY have the same significance asgiv'en above.

I I The first .step of our process comprises hydrolyz'ing ,a 2-f'uryl 'halomethyl ketone-hexamethy1enetetramine complex of the formula,

to the corresponding 2 -f uryl;.aminomethylketone acid addition salt. This hydrolysis is carried out in aqueous solution, using an inorganic mineral acid such as hydrochloric, hydrobromic, hydriodic, sulfuric or pho'sphoricacids as the hydrolytic agent. Due to the rather unstable nature of the 2- furylaminomethyl ketone product, the excess hydrgrlytic agent 'mustbe removed-either Spy distillation in the case of the volatile-acids w as.

or by precipitation as an insoluble metal salt in the case of. the non-volatile acids as soon as the reaction is complete. Due to the ease of removal by distillation in vacuo the hydrohalic acids are the preferred hyd-rolytic agents. Where it is desired to proceed with the second step of the process without isolation of the Z-furyl aminomethyl ketone compound, the excess hydrolytic agent need not be removed by the method set forth above but merely neutralized with a weakly alkaline substance such as an alkali metal acetate, phosphate, carbonate or bicarbonate. Regardless of the acid selected as the hydrolysis catalyst the Z-furyl aminomethyl ketone acid addition salt formed consists principally of the salt corresponding to the acid used in hydrolysis.

The hydrolysis reaction can be carried out at temperatures varying from about 0 to 50 C. However, we prefer to use a temperature of about 20 to 30 C. since in this temperature range the reaction proceeds at a reasonable rate and the danger ofdecomposition of the starting material and] or the final product is almost ata minimum.

The second step of the process comprises converting the mineral acid addition salt of the 2- furyl aminomethyl ketone, obtained in the first step of the process to the corresponding Z-furyl acylamidomethyl ketone of formula,

In carrying out this acylation an acid addition salt of the z-furyl aminomethyl ketone must be employedasthe starting material since the free bases of these amino ketones are rather unstable. 'I-Iowever, in order for :the acylation reaction .to

- action mixture and to acylate it. This is accomplished by carrying out the reaction in the presence of a weakly alkaline substance such as an alkali metal salt of an organic acid, an alkali or alkaline earth metal carbonate or bicarbonate, tertiary organic base, a hydroxide of an amphoteric metal, calcium hydroxide and the like. Some specific examples of such weakly alkaline substances are sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, calcium carbonate, magnesium carbonate, pyridine, quinoline triethylamine and aluminum hydroxide.

As acylating agents, acyl halides or acyl anhydrides can be employed in conjunction with either aqueous or non-aqueous reaction mediums.

The temperature of the reaction is not particularly critical and can be varied over a considerable range without any significant deleterious effect upon the yields of the final products. In general, temperatures varying from about C. to about 50 C. can be used although when a nonaqueous reaction mixture is employed the temperature can be increased slightly if desired.

The products of the invention are useful as intermediates in the preparation of other organic compounds. They are of particular value in the preparation of organic compounds possessing antibiotic activity against micro-organisms of the Rickettsia type.

The invention is illustrated by the following examples:

Example 1 150 g. of Z-furyl bromomethyl ketone-hexamethylenetetramine complex is added to 800 cc. of 6 N hydrochloric acid and the mixture allowed to stand at room temperature for about forty-five minutes. The reaction mixture is evaporated to dryness in vacuo to obtain the desired 2-furyl aminomethyl ketone hydrochloride which has the formula,

i O o-omNmnol Example 2 50 g. of 2-furyl aminomethyl ketone hydrochloride is added to a mixture of 500 ml. of pyridine and 85 ml. of crotonyl chloride. After standing at room temperature for one hour, the mixture is stirred into cold water. The 2-furyl crotonamidomethyl ketone which separates is recrystallized from aqeuous alcohol. This compound has the formula,

0 O 0 -CHzNHHJCH=CHCHg Example 3 50 ml. of 2-fury1 chloride is slowly added to a solution of 30 g. of Z-furyl aminomethyl ketone hydrochloride in 200 ml. of pyridine maintained at to C. After the temperature of the solution rises to about 25 C. the solution is poured into cold water. The 2-furyl furamidomethyl ketone which separates is recrystallized from aqueous dioxane. This compound has the formula,

t o-orrmmt o 0 Example 4 63 g. of 2-furyl aminomethyl ketone hydrochloride in 250 ml. of pyridine is treated with 70 g. of p-toluyl chloride and the resulting solution is stirred for one hour at room temperature. The mixture is poured into water and the Z-furyl ptoluamidomethyl ketone which separates is recrystallized from aqueous alcohol. This compound has the formula,

4 Example 5 60 g. of 2-furyl aminomethyl ketone hydro chloride in 250 ml. of pyridine is treated with 155 g. of acetoxyacetic anhydride. After stirring at room temperature for two and one-half hours, the solution is concentrated in vacuo to obtain a syrup which, on dilution with cold water, solidifies. The 2-furyl acetoxyacetamidomethyl ketone is crystallized from aqueous alcohol. This compound has the formula,

0 0 O O ("J-CHzNHHZCHOiLCH:

Example 6 350 g. of 5-nitro-2-furyl bromomethyl ketonehexamethylenetetramine complex is added to 1500 cc. of 6 N hydrochloric acid and the mixture allowed to stand at room temperature for one hour. The reaction mixture is evaporated to dryness in vacuo at room temperature to obtain the desired 5-nitro-2-furyl aminomethyl ketone hydrochloride. This product has the formula,

Example 7 Example 8 37.4 g. of 5-nitro-2-furyl aminomethyl ketone hydrochloride and 30 g. of sodium acetate are added to about ml. of dichloroacetic anhydride. The solution is stirred at 40-50 C. for one hour. Upon stirring into water, the solid 5-nitro-2-furyl dichloroacetamidomethyl ketone separates, and is recrystallized from aqueous alcohol. The formula of this compound is,

O O OaN O iL-CHrNH--CHCII Example 9 200 g. of 5-iodo-2-furyl bromomethyl ketonehexamethylenetetramine complex is added to 1 liter of 6 N hydrochloric acid and the mixture allowed to stand at room temperature for about one hour. The reaction mixture is evaporated to dryness in vacuo at room temperature to obtain the desired 5-iodo-2-furyl aminomethyl ketone hydrochloride of formula,

Example 10 A mixture consisting of 45 g. of 5-iodo-2-furyl aminomethyl ketone hydrochloride, 50 g. of benzoic anhydride and 6 g. of sodium acetate is heated to :about .45 c. and .stirred -.-as smau amounts of ice-and :watenare added from time to time. After :about one hour the :mixture is iiilut'e'd with water, cooled, adjus'tedzztopH v8 with sodium hydroxide and i the desired 51iodo.-2-.f.ur,yl .benzamidomethyl aketone :Which :separates collected. The product is washed with water and dried. I-tl has the ,formula,

:o I cH2NH-t -C Example 11 Example '12 27mg. :of --chloro-2 furyl aminomethyl ketone phosphate and; g. of cyanoacetyl chloride are stirred with 50 ml. of pyridine for one and onehalf hours at :room temperature. Upon; pouring the mixture into water, the solid 5-chloro-2- juryl ,oyanoacetamidomethyl ketone separates and is recrystallized from ethyl acetate. This compound has thezformula:

a "Cl-LO o omunocmou Example 13 115 g. of 5-bromo-2-furyl bromomethyl ketonehexamethylenetetramine complex is added to 700 ml. of 6 N sulfuric acid and the mixture is allowed to stand at room temperature for one hour. The solution is concentrated to about 100 ml. and poured into two volumes of ethanol. The 5-bromo-2-furyl aminomethyl ketone sulfate which separates is recrystallized from aqueous alcohol. This compound has the formula,

Example 14 53 g. of 5-bromo-2-furyl aminomethyl ketone sulfate and '70 g. of bromoacetyl bromide are stirred with 200 ml. of pyridine at room temperature for one-half hour. The solution is concentrated to 100 ml. and poured into cold water. The 5-bromo-2-furyl bromoacetamidomethyl ketone which separates is recrystallized from aqueous dioxane. This compound has the Example 15 175 g. of 5-methyl-2-furyl bromomethyl ketone-hexamethylenetetramine complex is added to 1 liter of 6 N hydrobromic acid and the resultne mixtur allowed to tand at room tempera ture for about forty-five minutes. Theweaction mixture is evaporated to dryness in vacuo to obtain the desired 5-methyl-2-furyl aminomethyl ketone hydrobromide :of formula,

.Example "16 5 5.5 g. of; semethylflefuryl aminomethyl "keton :hydrobromideis added, to; a .mixture consisting of is recrystallized from aqueous alcohol.

70 g. of dryjpyridineandfio gnoiphenyl acetyl chloride, keeping the temperature below about 5 C. After stirring for about one hour 1 liter of cold water is added andtheprecipitated product collected. The product thus obtained. is 5 -methyl-2 -furyl phenylacetamidomethyl ketone of formula,

Ewa'mple 17 31g. of ,5-methy1-2-furyljaminomethyl ketone hydrobromide and.26.g. of succinic anhydride are stirred-withlOO, ml..of pyridine at 510 C. for two hours. flhelsolutionis poured'into water, and the 5-methyle2furyl succinamidomethyl ketone is precipitated by. acidification of the resulting solution with 6 N hydrochloric acid. This material This compound has theformula,

Example 18 i 60 a. of '5-ethyl-2-furyl'bromomethyl ketonev hexamethylenetetramine complex is added to300 "ml. of "20%'hydriodic acid and'the mixture is kept at'room'temperature for one hour. Evaporation of the solution'gives'a residue of '5-ethyl- 2-furyl aminomethyl ketone hydriodide which is crystallized from aqueous methanol. This compound has the formula,

Example 19 1'7 g. of 5-ethyl-2-furyl aminomethyl ketone hydriodide and 14.5 g. of sodium acetate are stirred with '75 g. of methoxyacetic anhydride at 50 C. for forty-five minutes. The mixture is poured into cold water whereupon the 5-ethyl-2- furyl methoxyacetamidomethyl ketone separates as an oil. After this oil crystallizes it is recrystallized from aqueous alcohol. This compound. has the formula,

, o I o oim L ltLom-Nn- -omoom Example 20 31 g. of Z-furyl aminomethyl ketone hydrochloride and 39.5 g. of nicotinoyl chloride are stirred with 200 ml. of pyridine for one and one-half hours. The solution is evaporated to about m1. and poured into water. The Z-furyl 3-nicotinamidomethyl ketone which separates is recrystallized from aqueous dioxane. pound has the formula,

CLLCWE The 2-furyl halomethyl ketone-hexamethylenetetramine complexes used as starting materials in the practice of the invention can be prepared by the reaction of a Z-furyl halomethyl ketone with hexamethylenetetramine in an inert organic solvent. This general process can be diagrammatically depicted as follows:

0 Rio (J-crux (CHmN4 where R and X have the same significance as given above.

This com- The following examples serve to illustrate the Y application of this general method to the preparation of some of the specific starting materials used in the foregoing examples:

a. 228 g. of 5-nitro-2-furyl bromomethyl ketone dissolved in a small amount of carbon tetrachloride is added to 150 g. of hexamethylenetetramine in 1 liter of carbon tetrachloride. The mixture is allowed to stand at room temperature for about three hours and the 5-nitro-2-furyl' bromomethyl ketone hexamethylenetetramine complex which separates collected, washed with a little chloroform and dried. The formula of this product is,

b.'75 g. of hexamethylenetetramine dissolved in 10000. of carbon tetrachloride is added to 95 g. of 2-fury1 bromomethyl ketone in 400 cc. of car- 'bon tetrachloride. The solid reaction product begins to separate almost immediately and the temperature of the reaction mixture rises somewhat. After allowing the mixture to stand for aboiit two hours the Z-furyl bromomethyl ketonehexamethylenetetramine complex is collected, washed with a little carbon tetrachloride and dried. The formula of this product is,

0 O -CHKCHQaNLBI' What we claim is: 1. A compound of the formula,

where R is a member of the class consisting of hydrogen, nitro, halogen and lower alkyl radicals and R is a member of the class consisting of hydrogen, I-LHY, and acyl radicals, said HY group being one equivalent of a strong mineral acid.

2. A compound of the formula,

where R is a member of the class consisting of hydrogen, nitro, halogen, and lower alkyl radicals.

3. 2-furyl acetamidomethyl ketone. 4. B-nitro-Z-furyl acetamidomethyl ketone. 5. 5-nitro 2 furyl dichloroacetamidomethyl ketone.

6. 5-bromo-2-furyl bromoacetamidomethyl ketone.

7. 5-iodo-2-furyl benzamidomethyl ketone.

LOREN M. LONG. NICKOLAS D. JENESEL.

No references cited. 

1. A COMPOUND OF THE FORMULA, 